Intraocular pressure sensing material, devices, and uses thereof

ABSTRACT

Described herein are eye implants that can include a pressure-responsive material that can be capable of changing color in response to pressure exerted on it. Also described here are methods of implanting and using the eye implants described herein to monitor intraocular pressure in a subject. The pressure-responsive material can be used to diagnose and monitor human or animal subjects.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.17/051,051, having the title “INTRAOCULAR PRESSURE SENSING MATERIAL,DEVICES, AND USES THEREOF”, filed on Oct. 27, 2020, which is the 35U.S.C. § 371 national stage application of PCT Application No.PCT/US2019/038193, filed Jun. 20, 2019, where the PCT claims priorityto, and the benefit of, U.S. provisional application entitled“INTRAOCULAR PRESSURE SENSING MATERIAL, DEVICES, AND USES THEREOF”having Ser. No. 62/687,614, filed Jun. 20, 2018, both of which areherein incorporated by reference in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under HDTRA-1-15-1-0022awarded by the Department of Defense/Defense Threat Reduction Agency.The Government has certain rights in this invention.

BACKGROUND

Measurement of intraocular pressure is important for glaucoma and manyeye diseases. Currently, indirect methods are used for measuringintraocular pressure which involve external contact to the eye. However,the results are variable based upon the corneal thickness and otherstructural differences in the wall of the eye. As such, there exists aneed for improved eye monitoring devices and techniques.

SUMMARY

In embodiments of the present disclosure, disclosed herein areintraocular implants. Intraocular implants as described herein cancomprise a pressure-responsive material, the pressure-responsivematerial comprising chromogenic photonic crystals, wherein thechromogenic photonic crystals change confirmation resulting in a changeof color of the pressure-responsive material in response to an amount ofpressure exerted on the shape-memory chromogenic photonic crystals.

In embodiments according to the present disclosure, thepressure-responsive material can be a first color at a normalphysiologic intraocular pressure of about 10 to about 20 mm Hg. Thepressure-responsive material can be second color at an elevatedintraocular pressure of greater than about 20 mm Hg. Thepressure-responsive material can be a third color at a reducedintraocular pressure of less than about 10 mm Hg.

In embodiments according to the present disclosure, the implant can bean intraocular lens. In embodiments according to the present disclosure,the implant can be a glaucoma drainage device.

In embodiments according to the present disclosure, the pressureresponsive material can be coated on a surface of a drainage tube of theglaucoma drainage device.

In embodiments according to the present disclosure, the surface can bean outer surface of the drainage tube. In embodiments according to thepresent disclosure, the surface can be an inner surface of the drainagetube.

In embodiments according to the present disclosure, the implant cancomprise one or more layers of the pressure-responsive material coatedon all or part of a surface of the implant or component thereof.

In embodiments according to the present disclosure, each of the one ormore layers is about 0.5 mm to about 3 mm thick.

In embodiments according to the present disclosure, thepressure-responsive material can be integrated with a component of theimplant.

In embodiments according to the present disclosure, the implant cancomprise one or more layers of the pressure-responsive material embeddedin all or part of a surface of the implant or component thereof. Inother embodiments, the implant can include the pressure-responsivematerial in the body of the implant.

In embodiments according to the present disclosure, the pressureresponsive material can comprise photonic crystals embedded in (e.g.encapsulated in) a hydrogel.

Also described herein are methods. In embodiments according to thepresent disclosure, methods as described herein comprise: implantinginto the eye of a subject in need thereof an implant according to thepresent disclosure.

In embodiments according to the present disclosure, methods can furthercomprise detecting the color of the pressure-responsive material of theimplant without contacting the eye.

In embodiments according to the present disclosure, methods can furthercomprise quantitatively measuring the color of the pressure-responsivematerial of the implant using a spectrometer.

In embodiments according to the present disclosure, a subject in needthereof can be a human or a canine. In embodiments according to thepresent disclosure, the subject in need thereof has or is at risk forocular hypertension. In embodiments according to the present disclosure,the subject in need thereof has glaucoma.

In embodiments according to the present disclosure, a method ofmeasuring intraocular pressure in a subject having an implant isdescribed herein, the method comprising: detecting the color of thepressure-responsive material of the implant without contacting the eye.The subject can be a human or a canine. The subject can have ocularhypertension or can be at risk for ocular hypertension. The subject inneed thereof can have glaucoma.

In embodiments according to the present disclosure, methods as describedherein can comprise quantitatively measuring the color of thepressure-responsive material of the implant using a spectrometer orother spectral monitoring device, for example a smartphone with anapplication configured for spectrometry.

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is tobe understood that this disclosure is not limited to particularembodiments described, and as such may, of course, vary. It is also tobe understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the disclosure, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, the preferredmethods and materials are now described.

All publications and patents cited in this specification are cited todisclose and describe the methods and/or materials in connection withwhich the publications are cited. All such publications and patents areherein incorporated by references as if each individual publication orpatent were specifically and individually indicated to be incorporatedby reference. Such incorporation by reference is expressly limited tothe methods and/or materials described in the cited publications andpatents and does not extend to any lexicographical definitions from thecited publications and patents. Any lexicographical definition in thepublications and patents cited that is not also expressly repeated inthe instant application should not be treated as such and should not beread as defining any terms appearing in the accompanying claims. Thecitation of any publication is for its disclosure prior to the filingdate and should not be construed as an admission that the presentdisclosure is not entitled to antedate such publication by virtue ofprior disclosure. Further, the dates of publication provided could bedifferent from the actual publication dates that may need to beindependently confirmed.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure. Any recited method can be carried out in the order of eventsrecited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwiseindicated, techniques of molecular biology, microbiology, organicchemistry, biochemistry, physiology, cell biology, cancer biology, andthe like, which are within the skill of the art. Such techniques areexplained fully in the literature.

Definitions

As used herein, “about,” “approximately,” and the like, when used inconnection with a numerical variable, can generally refers to the valueof the variable and to all values of the variable that are within theexperimental error (e.g., within the 95% confidence interval for themean) or within +/−10% of the indicated value, whichever is greater.

The term “biocompatible”, as used herein, refers to a material thatalong with any metabolites or degradation products thereof that aregenerally non-toxic to the recipient and do not cause any significantadverse effects to the recipient. Generally speaking, biocompatiblematerials are materials that do not elicit a significant inflammatory orimmune response when administered to a patient.

As used herein, “organism”, “host”, and “subject” refers to any livingentity comprised of at least one cell. A living organism can be assimple as, for example, a single isolated eukaryotic cell or culturedcell or cell line, or as complex as a mammal, including a human being,and animals (e.g., vertebrates, amphibians, fish, mammals, e.g., cats,dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears,primates (e.g., chimpanzees, gorillas, and humans).

As used herein, the terms “treating” and “treatment” can refer generallyto obtaining a desired pharmacological and/or physiological effect. Theeffect can be, but does not necessarily have to be, prophylactic interms of preventing or partially preventing a disease, symptom orcondition thereof, such as abnormal eye pressure and/or diseases andconditions associated with abnormal eye pressure (including but notlimited to glaucoma). The effect can be therapeutic in terms of apartial or complete cure of a disease, condition, symptom or adverseeffect attributed to the disease, disorder, or condition. The term“treatment” as used herein covers any treatment of glaucoma, ocularhypertension (elevated intraocular eye pressure), or reduced intraoculareye pressure, in a subject, particularly a human or a canine, and caninclude any one or more of the following: (a) preventing the diseasefrom occurring in a subject which may be predisposed to the disease buthas not yet been diagnosed as having it; (b) inhibiting the disease,i.e., arresting its development; and (c) relieving the disease, i.e.,mitigating or ameliorating the disease and/or its symptoms orconditions. The term “treatment” as used herein can refer to boththerapeutic treatment alone, prophylactic treatment alone, or boththerapeutic and prophylactic treatment. Those in need of treatment(subjects in need thereof) can include those already with the disorderand/or those in which the disorder is to be prevented. As used herein,the term “treating”, can include inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease, disorder, or conditioncan include ameliorating at least one symptom of the particular disease,disorder, or condition, even if the underlying pathophysiology is notaffected, such as treating the pain of a subject by administration of ananalgesic agent even though such agent does not treat the cause of thepain.

Discussion

Measurement of intraocular pressure is important for diagnosis andtreatment of glaucoma and many other eye diseases. Currently, indirectmethods are used for measuring intraocular eye pressure. These methodsinvolve external eye contact to the eye. Thus, current methodologiesproduce results that are variable and based upon the corneal thicknessand other structural differences in the wall in the eye that can changeover time. As such, current methodologies can produce inaccurate resultswhich can negatively impact eye health evaluations and diseasemonitoring and treatment.

With that said, described herein are materials, which can bebiocompatible, that can be pressure-responsive and incorporated inintraocular lenses and/or other eye devices that can be capable ofmonitoring eye pressure. The materials can be capable of changing colorin response to pressure exerted on the material. The color of thematerial can be quantitatively measured and can provide a direct andnon-contact method of measuring intraocular pressure. Othercompositions, compounds, methods, features, and advantages of thepresent disclosure will be or become apparent to one having ordinaryskill in the art upon examination of the following drawings, detaileddescription, and examples. It is intended that all such additionalcompositions, compounds, methods, features, and advantages be includedwithin this description, and be within the scope of the presentdisclosure.

Described herein are devices that can be implanted into a subject, suchas in the eye or eye region, that can include a pressure-responsivematerial. The pressure responsive material can be composed ofchromogenic photonic crystals that can be based on smart shape memorypolymers. The chromogenic photonic crystals can be as described in Leo,S. et al. 2018. Chromogenic Photonic Crystal Sensors Enabled byMultistimuli-Responsive Shape Memory Polymers” Small 14(12):1703515,which is incorporated by reference as if fully set forth herein. Inembodiments according to the present disclosure, chromogenic photoniccrystal sensors are based on smart shape memory polymers (SMPs)comprising polyester/polyether-based urethane acrylates blended withtripropylene glycol diacrylate, which exhibit nontraditionalall-room-temperature shape memory (SM) effects.

The pressure-responsive material can change color when differentpressures are exerted on it. Thus, when incorporated in a device that isimplanted into an eye, the intraocular pressure can be exerted on thepressure-responsive material incorporated in the device. Thepressure-responsive material can change confirmation depending on theamount of pressure exerted on it by the eye contents and thus be aparticular color depending on that exerted pressure. The color can bequalitatively measured by shining a light into the eye and onto thepressure-responsive material implanted in the eye and observing thecolor of the pressure-responsive material. The color can be measuredquantitatively using spectral analysis to determine the color of thepressure-responsive material. Any suitable device that can externallymeasure the color spectrally can be used. In some aspects, the device isa hand held spectrometer or smartphone with an imaging device. Suchdevices are generally known and available. For example, a color analysisapp (e.g., Color Mate Version 1.2.2) installed on a smartphone can beused in analyzing the RGB values of the sensor in response to differentintraocular pressures.

The color of the pressure-responsive material can be tuned by includingsilica particles with different diameters. Experiments have confirmedthat the pressure-responsive materials of the present disclosure anddevices including the pressure-responsive material can cover the wholevisible spectrum range from 400 to 700 nm. For example, by includingsilica particles having an average diameter of about 500 to 500 nm,about 400 to 450 nm, and about 600 to 650 nm in the samepressure-responsive material, the material can appear green, blue, andred, respectively. The visible color can correlate to a pressure.

The color of the pressure-responsive material can be directly correlatedto the intraocular pressure. In some aspects, at normal physiologicintraocular pressure (about 10 to about 20 mm Hg) the color of thepressure-responsive material can range from about 500 nm to 550 nmcorresponding to a green color. The color of the pressure-responsivematerial can range be a first color. An intraocular pressure that isabove normal (elevated intraocular eye pressure) can be anything overabout 20 mm Hg. At elevated intraocular pressures ranging from about 20mm Hg to about 30 mm Hg or more, the color of the pressure-responsivematerial can be a second color that is different from that at normalphysiological pressure. The color of the pressure-responsive materialcan range from about 400 nm to 450 nm corresponding to a blue color. Ifa subject is not having symptoms of an eye disease such as glaucoma buthas an elevated intraocular pressure, this can be referred to as ocularhypertension. These individuals are at risk for developing an eyedisease, such as glaucoma, and can require more intensive monitoring.

Ocular hypertension is not the only pressure abnormality that can leadto eye problems. In some cases, such as after eye surgery (e.g. glaucomasurgery) or episodes of ocular ischemia, the intraocular pressure canbecome too low. A condition called hypotony can be diagnosed if theintraocular pressure decreases to about 6 mm Hg or less or in some casesabout 10 mm Hg or less. When intraocular pressure is too low it cancause distortions of the retina, lens, and cornea that can degradevision and lead to vision loss. At reduced intraocular pressures rangingfrom about 4 mm Hg to about 10 mm Hg, the color of thepressure-responsive material can be a third color that is different thanthe color at normal physiological pressure or elevated pressure. Thecolor of the pressure-responsive material can range from about 600 nm to650 nm corresponding to a red color.

As described above, the pressure-responsive material can be coated inone or more layers on or incorporated into at least a portion of animplantable intraocular device. The pressure-responsive material can becoated on or incorporated into at least a portion of an intraocular lensor other prosthetic devices. In some aspects, a layer of thepressure-responsive material can range from about 0.1 mm to 0.5 mm, 0.5mm to about 3 mm, about 1 mm to about 2.5 mm, about 1.5 mm to about 2 mmthick. Suitable intraocular lenses and prosthetics are generally knownand available.

The implantable device can include the pressure-responsive material inthe body of the implant. In the case of an intra-ocular lens implant,for example, the pressure-responsive material could be placed in theouter part of the optic, thus leaving the central visual axis clear ofany color change or potentially different refractive index material toprevent or minimize visual clarity issues while still undergoingpressure-responsive color change.

Glaucoma can be treated by implanting a device that helps keep thesurgically-created drainage opening from healing and closing down. Manyincorporate a tube through which the aqueous eye fluid passes. Othersare solid and promote the flow of fluid along the surface of theimplant. Newer implants commonly referred to as micro-invasive glaucomasurgery devices are tiny drainage implants (e.g. the Cypass Microstentfrom Alcon, AqueSys's XEN Gel Stent, MicroShunt Glaucoma Drainage Systemby InnFocus Inc., STARflo Glaucoma Implant and MlNlject from iSTarMadical SA, and the Hydrus Microstent form Ivantis) have also beendeveloped and incorporate tiny drainage conduits (e.g. stents) that cancreate a permanent conduits for moving eye fluids and decreasingintraocular pressure. Other various implants for treatment of glaucomaare known. The pressure-responsive material can be coated on orincorporated in any of the components of an implant for treatment ofglaucoma. In some aspects the pressures-responsive material can beincorporated on or on the inside of the drainage stent or tube of theimplant.

In use, the pressure-responsive material can be coated on an existingeye implant device described above. In other aspects, thepressure-responsive material can be coated on or otherwise incorporatedin an eye implant device at the point of manufacture of the device orany of its components or material. The eye implant device can beinserted into an eye of a subject using any suitable surgical techniquethat is appropriate for that particular eye implant and subject. Thiscan be determined by the medical practitioner. After implantation, thepressure of the subject's eye containing the eye implant device can bemeasured qualitatively by viewing the color of the pressure-responsivematerial using suitable eye examination devices and equipment (e.g.ophthalmoscope, ophthalmic lope, otoscopes, etc.) and/or qualitativelyby using a suitable spectrophotometer device. These are discussedelsewhere herein. The method of pressure measurement when thepressure-responsive material and devices incorporating thepressure-responsive material is employed does not require contact withthe eye or subject to changes in the structures of the eye. Further,this measurement method does not require any eye dilation or otheruncomfortable procedures to allow measurement. Further, the devicesherein allow for measurement of eye pressure at any time. This can be anadvantage of current techniques as the pressure of the eye can changethroughout the day. The devices and techniques described herein can thusallow for improved monitoring of the eye, particularly a diseased eye,and improve care of the subject.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. An intraocular implant comprising: a pressure-responsivematerial, the pressure-responsive material comprising chromogenicphotonic crystals, wherein the chromogenic photonic crystals changeconformation resulting in a change of color of the pressure-responsivematerial in response to an amount of pressure exerted on theshape-memory chromogenic photonic crystals and wherein the chromogenicphotonic crystal comprise smart shape memory polymers (SMPs), whereinthe implant is an intraocular lens.
 2. The intraocular implant of claim1, wherein the pressure-responsive material is a first color at a normalphysiologic intraocular pressure of about 10 to about 20 mm Hg, whereinthe first color ranges from about 500 nm to 550 nm corresponding to agreen color.
 3. The intraocular implant of claim 2, wherein thepressure-responsive material is a second color at an elevatedintraocular pressure of greater than about 20 mm Hg, wherein the secondcolor ranges from about 400 nm to 450 nm corresponding to a blue color.4. The intraocular implant of claim 3, wherein the pressure-responsivematerial is a third color at a reduced intraocular pressure of less thanabout 10 mm Hg, wherein the third color ranges from about 600 nm to 650nm corresponding to a red color.
 5. An intraocular implant comprising: apressure-responsive material, the pressure-responsive materialcomprising chromogenic photonic crystals, wherein the chromogenicphotonic crystals change conformation resulting in a change of color ofthe pressure-responsive material in response to an amount of pressureexerted on the shape-memory chromogenic photonic crystals and whereinthe chromogenic photonic crystal comprise smart shape memory polymers(SMPs), wherein the implant is a glaucoma drainage device.
 6. Theintraocular implant of claim 5, wherein the pressure responsive materialis coated on a surface of a drainage tube of the glaucoma drainagedevice.
 7. The intraocular implant of claim 6, wherein the surface is anouter surface of the drainage tube.
 8. The intraocular implant of claim6, wherein the surface is an inner surface of the drainage tube.
 9. Anintraocular implant comprising: a pressure-responsive material, thepressure-responsive material comprising chromogenic photonic crystals,wherein the chromogenic photonic crystals change conformation resultingin a change of color of the pressure-responsive material in response toan amount of pressure exerted on the shape-memory chromogenic photoniccrystals and wherein the chromogenic photonic crystal comprise smartshape memory polymers (SMPs), wherein the implant comprises one or morelayers of the pressure-responsive material embedded in all or part of asurface of the implant or component thereof.
 10. An intraocular implantcomprising: a pressure-responsive material, the pressure-responsivematerial comprising chromogenic photonic crystals, wherein thechromogenic photonic crystals change conformation resulting in a changeof color of the pressure-responsive material in response to an amount ofpressure exerted on the shape-memory chromogenic photonic crystals andwherein the chromogenic photonic crystal comprise smart shape memorypolymers (SMPs), wherein the implant comprises one or more layers of thepressure-responsive material coated on all or part of a surface of theimplant or component thereof.
 11. The intraocular implant of claim 10,wherein each of the one or more layers is about 0.5 mm to about 3 mmthick.
 12. An intraocular implant comprising: a pressure-responsivematerial, the pressure-responsive material comprising chromogenicphotonic crystals, wherein the chromogenic photonic crystals changeconformation resulting in a change of color of the pressure-responsivematerial in response to an amount of pressure exerted on theshape-memory chromogenic photonic crystals and wherein the chromogenicphotonic crystal comprise smart shape memory polymers (SMPs), whereinthe pressure-responsive material is integrated with a component of theimplant.
 13. An intraocular implant comprising: a pressure-responsivematerial, the pressure-responsive material comprising chromogenicphotonic crystals, wherein the chromogenic photonic crystals changeconformation resulting in a change of color of the pressure-responsivematerial in response to an amount of pressure exerted on theshape-memory chromogenic photonic crystals and wherein the chromogenicphotonic crystal comprise smart shape memory polymers (SMPs), whereinthe pressure-responsive material comprises a hydrogel.